EVIDENCE THAT DARK-PHASE HYPERPHAGIA INDUCED BY NEUROTOXIN 6-HYDROXYDOPAMINE MAY BE DUE TO DECREASED LEPTIN AND INCREASED NEUROPEPTIDE-Y SIGNALING

Hyperphagia and obesity can be experimentally induced in rodents by mi croinjection of 6-hydroxydopamine (6-OHDA) into the ventral noradrener gic bundle (VNAB) to interrupt efferent catecholaminergic pathways to the hypothalamus. Since hypothalamic neuropeptide Y (NPY) is implicate d in the control of ingestive behavior, we evaluated hypothalamic NPY activity in this model of obesity. Adult male rats injected bilaterall y with 12 mu g of 6-OHDA in the VNAB displayed an enhanced rate of bod y weight gain and selective dark-phase hyperphagia that started at abo ut 10 days postinjection and persisted for the entire duration of the experiment. NPY gene expression, assessed by ribonuclease protection a ssay, was significantly higher in the hypothalami of 6-OHDA-treated hy perphagic rats during the dark phase (p < 0.01 vs. levels during the l ight phase and in control, vehicle-injected rats). We also evaluated g ene expression of NPY Y1 and Y5 receptors, receptor subtypes reported to mediate NPY-induced feeding. The dark-phase increase in NPY mRNA wa s accompanied by the concomitant upregulation of NPY Y5R gene expressi on, but not of Y1R mRNA levels. Leptin, the peripheral hormone secrete d by adipocytes, is believed to maintain body weight and inhibit food intake, most likely by suppressing hypothalamic NPY activity. Evaluati on of leptin gene expression in the epididymal fat revealed that the u pregulation of leptin mRNA noted during the dark phase in control rats did not occur in 6-OHDA-treated rats. These observations implied that the normal restraint on NPY and feeding exercised by leptin in contro l rats may be abrogated in 6-OHDA-treated hyperphagic rats due to insu fficient levels of leptin. If so, administration of leptin should inhi bit food intake in these rats. Indeed, injection of leptin (2 mg/kg, i ntraperitoneally (i.p.)) on 2 consecutive days reduced 24-h food intak e by 25% and significantly reduced body weight. These results suggest that the nocturnal hyperphagia and resultant obesity induced by 6-OHDA injected into the VNAB may be attributed to leptin deficiency concomi tant with increased hypothalamic NPY. (C) 1998 Elsevier Science Inc.